CS245151B1 - Method of 6-substituted n-((5r,8s,10r)-8-ergolinyl)-n,n'-diethylureas production - Google Patents

Description

A preferred process for preparing 6-substituted N - [(5R, 8S, 10R) -8-ergolinyl] -N, N- diethylureas of Formula I

(I) wherein R represents a C 2 -C 4 straight-chain or branched alkyl group consisting of the reaction of (5R, 8S, 10R) -6-alkyl-8-ergolinyliaocyanate of formula II with diethylamine. The compounds of Formula I are important inhibitors of prolactin and growth hormone secretion and gonadotropin eecretion stimulators.

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245'51

The invention relates to a process for the preparation of 6-substituted N - ((5R, 8S, 10R) -8-ergolinyl) -N'-N'-diethylureas of the formula I

in which R represents a straight-chain or branched alkyl group having 2 to 4 carbon atoms, and salts thereof with pharmaceutically acceptable acids.

The compounds of formula I contain three chiral centers in their molecule, asymmetric carbons at the 5, 8 and 10 positions, the hydrogen atom at the beta position and the configuration at this carbon is 5Rj the urea residue at the carbon position is at alpha and the configuration at this carbon is 8S ; the hydrogen atom on the carbon is in the alpha position and the configuration on said carbon is 10R.

The ergolines of the formula I exhibit a potent inhibitory effect on prolactin and growth hormone secretion and a stimulating effect on gonadotropin secretion in experimental animals. These pharmacological effects can be used in human therapy, for example to stop postpartum lactation, in the treatment of galactorrhoel, amenorrhoea, hormone-dependent breast tumors, acromegaly and parkineonium, or in veterinary therapy, for example, to stop lactation and induce heat in livestock. According to a known method (German patent 3 016 691), the compounds of the formula I can be prepared by catalytic hydrogenation of the corresponding N- (9,10-didehydroergolinyl) -N ', N'-ethyl ureas.

In the known manner, however, the compounds of formula 1 are obtained in low yield, since catalytic hydrogenation of 9,10-didehydro-8α-erg61inylureas results in a mixture of 1 (XH and IQrf-H isomers from which the desired 10-isomer of formula 1 must be obtained). In addition, the preparation of the 9,10-unsaturated ergolinylureas from 6-nor-6-alkyllysergic acid methyl esters according to said NSR patent is also time-consuming and unsatisfactory in yield.

The present inventors have found that the compounds of the formula I can advantageously be produced, in high purity and in several times higher yields than according to the known processes, by reaction of diethyl amine with the corresponding 8 -ergolinylisocyanates of the formula II below. The starting isocyanates can be prepared from known (5R, 8S, 10R) -6-alkyl-8-ergolinecarbosylic acid hydrazides (U.S. Pat. No. AO 206 142) by general methods (see, for example, U.S. Pat. No. AO 156 178),

According to the invention, the 6-substituted N- (5R, 8S, 1OR) -8-ergolinyl-N *, N * -diethylureas of the formula I in which R is as defined above are produced by producing f (5R, 8S). (10 (i) -6-alkyl-8-ergolinyl) isocyanate of formula II

(II), wherein R is as defined above, is reacted in an inert solvent with diethylamine, and the compound of formula (I) is optionally converted into an addition salt and a pharmaceutically acceptable acid.

The starting ioocyanates of the formula II can advantageously be prepared in situ from (5R, 8S, 10R) -6-alkyl-8-ergolinecarboxylic acid hydrazides. The reaction ae is preferably carried out by a damping process by converting said hydrazide with nitrous acid or a nitrous acid ester, in the presence of a strong inorganic acid, into a floated azide which is taken up in alkaline water-immiscible inert solvent after alkalization. at 70 DEG-100 DEG C. by thermal decomposition to give the isocyanate of formula II which is reacted without isolation with diethylamine.

Suitable inert solvents include ether such as diethyl ether or diisopropyl ether, aromatic hydrocarbons such as benzene or toluene, or chlorinated, saturated or unsaturated hydrocarbons such as chloroform, tetrachloromethane, tetrachloroethane or trichlorethylene, or mixtures of these solvents.

The reaction of the ioocyanate of the formula II with β diethylamine is carried out by treating 1 to 10 mol equivalents, preferably 4 to 5 mol equivalents, of diethylamine with a solution of isocyanate in an organic solvent obtained by the above process. The reaction is carried out at a temperature of 0 to 120 ° C, preferably at 70 to 2100 ° C, and a reaction time of 1 to 24 hours.

The resulting urea (I) is isolated from the reaction mixture by conventional separation and purification procedures, for example by evaporation of the organic solvent used and chromatography and / or crystallization of the crude products obtained.

The 6-substituted 8-ergolinylureas of the formula I are colorless crystalline substances of a basic nature which give the salts of the editorial salts with strong inorganic and organic acids. For therapeutic purposes, water-soluble salts with pharmaceutically acceptable, non-toxic acids such as hydrochloric, sulfuric, methanesulfonic, ethanesulfonic, maleic, malic, tartaric, citric, terebic and the like are suitable. Said salts can be prepared by treating at least 1 mol equivalents of acid to 1 mol equivalents of a compound of formula I in a suitable inert solvent, preferably methanol, ethanol, water or mixtures thereof.

The process for the preparation of the 6-substituted 8-ergolinylureas of the general formula (I) is illustrated by the following non-limiting examples. The melting points of the compounds are determined on the Kofler block and are given, as with other temperature data, in ° C. The specific rotational values given refer to crystalline solvent-free substances, and yields are given in percent by weight.

He did

N - {(5R, 8S, 10R) -6-n-propyl-8-ergolinyl) -N ', N'-diethylurea

To a solution of 0.56 g (1.8 mmol) of (5R, 8S, 10R) -6-n-propyl-8-ergolinylcarboxylic acid hydrazides in 18 ml (1.8 mmol) of 0.1 M hydrochloric acid was stirred with stirring and while cooling to +1 to + -5 ° C, 1.8 ml (1.8 mmol) of a 1M sodium nitrite solution is added dropwise, then 11 ml (2.2 mmol) is added dropwise at the same temperature over about 3 minutes. Hydrochloric acid, and the mixture was stirred at this temperature for a further 15 minutes.

The reaction mixture was basified with 1M sodium bicarbonate solution, the base azide was taken up in 350 ml of benzene and the benzene extract was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate is heated to reflux for 10 min, under a nitrogen atmosphere and free of atmospheric moisture. A solution of 1 ml (7.2 mmol) of diethylamine in 5 ml of benzene was added to the obtained isocyanate solution and the reaction mixture was heated under reflux for 5 min. The solution was allowed to stand for 20 h at room temperature, then the solvent was distilled off under reduced pressure, and the residue (0.66 g; yield 99%) was chromatographed on an alumina column using chloroform as eluent.

From the uniform front fraction, the solvent was distilled off under reduced pressure and the residue (0.45 g, yield 68.1%) and recrystallized from ethanol. The title compound is obtained in the form of colorless crystals which initially melt at 82-84 ° C, solidify again with further heating and melt at 132-134 ° C. The substance contains 2 molecules of crystalline bound ethanol which loses on drying at 78 ° C and 13.3 Pa; optical rotation Wβ ⁰ = + 35 ° (c = 0.2, pyridine).

Example 2

N- ((5R, 8S, 10R) -6-n-propyl-8-ergolinyl) -N ', N'-diethyl urea hydrogen maleate

To a saturated solution of 0.184 g (0.5 mmol) of urea prepared as described in Example 1 in ethanol and treated with a solution of maleic acid (0.064 g, 0.55 mmol) in a minimum volume of ethanol, and the solution was crystallized.

Hydrogenmaleinan precipitated base was filtered off and dried, yield 0.15 g (62%) of solid, mp 180-182 ° C (<* ·) = ^»0 -15.2 (c = 0.5, methanol).

P-Example 3

Using the method described in Example 1, but using the corresponding (5R, 8S, 10R) -8-ergolinecarboxylic acid 6-substituted hydrazide, the following 6-n-propyl-8-ergolyncarboaylic acid was ground to 6-n-propyl-8-ergolyncarboaylic acid. -substituted N - ((5R, 8S, 10R) -8-ergolinyl) -N-N *, N'-diethylureas

N - ((5R, 8S, 10R) -6-ethyl-8-erealinyl) -N *, N-diethylurea, yield 70%, m.p.

197-199 ° C (from ethanol), = + 24.9 ° (c = 0.25, pyridine);

N- ((5R, 8S, 10R) -6-n-butyl-ergolinyl) -N ', N'-diethylurea, yield 73%, mp 95-98 ° C (from 90% ethanol), (X.)' 0 _B + 37.4 ° _(c = _0, 25, pyridine).

FOREWORD OF THE INVENTION

A process for the preparation of 6-substituted N - ((5R, 8S, 10R) -8-ergolinyl) -1'-N'-urea diets

Claims (3)

A process for the preparation of 6-substituted N - ((5R, 8S, 10R) -8-ergolinyl) -1 ', N'-diethyrea ureas of the general formula 1 (I) wherein R represents a straight-chain or branched alkyl group having 2 to 4 carbon atoms, and their salts with pharmaceutically acceptable acids, characterized in that the 6-aubstituted (5R, 8S, 10R) - &lt; - &gt; N = C - O (II) in which R is as defined above, is reacted with diethylamine, and the urea obtained of formula I is optionally converted into a salt with a pharmaceutically acceptable acid. 2. A process according to claim 1, wherein the inert organic solvent is ethers such as diethyl ether, aromatic hydrocarbons such as benzene or toluene, or chlorinated aliphatic saturated or unsaturated hydrocarbons such as chloroform, tetra-chloromethane, tetrachloroethane or trichlorethylene, or mixtures thereof. solvents. 3. The process according to claim 1, wherein the conversion of the isocyanate of formula II to the substituted diethylmethylamine of formula I is carried out by treating with 1 to 10 molar equivalents, preferably 4 to 5 mol equivalents, of diethylamine to 1 mol equivalent of isocyanate in organic solvent at 0 to 120 °. C, preferably at 70 to 100 ° C.